Although manganese (Mn) is an essential element, high levels of exposure can cause symptoms including cognitive and fine motor deficits in children. Studies have demonstrated that manganese overexposure leads to alterations in subcortical motor circuits, particularly basal ganglia and dopamine neuron impairments. Primary motor cortex (M1) receives input from subcortical motor circuits known to be affected by Mn overexposure, and changes in M1 excitatory synapse dynamics occur during fine motor skill learning. This raises the possibility that M1 could be affected by developmental Mn exposure, yet little is known about the effects of Mn exposure on synapses in the cortex. Recent studies have shown that fine motor deficits induced by developmental Mn exposure in rodents are alleviated with methylphenidate (MPH) treatment. However, it is not known whether MPH affects synapse plasticity in M1. We will address this gap in knowledge by using a fine motor skill learning paradigm coupled with in vivo two-photon and fixed-tissue imaging of synapses in M1 and pharmacogenetic activation of mesocortical dopamine neurons to investigate the synaptic, circuit, and behavioral effects of developmental Mn exposure and post-exposure MPH treatment in mice. We hypothesize that subcortical alterations caused by developmental Mn exposure give rise to M1 synapse disruptions and fine motor learning and performance dysfunction, and that MPH restores M1 synapse dynamics together with fine motor function. To address this hypothesis, we will use a mouse model of early postnatal Mn exposure to: 1) determine whether fine motor skill learning and performance impairments are associated with alterations in M1 spine dynamics following developmental postnatal Mn exposure in mice, and determine the effects of a methylphenidate regimen on motor learning and performance and M1 spine dynamics; 2) determine whether thalamocortical inputs to M1, which relay output of basal ganglia circuits, are disrupted following developmental Mn exposure; and 3) determine whether markers of dopaminergic neurotransmission are altered in M1, or whether increasing activity of mesocortical dopamine neurons improves fine motor function or impacts M1 synapses following developmental Mn exposure. Together, these experiments will advance our understanding of how developmental Mn affects the synapses and circuits of M1 associated with fine motor deficits. In addition, the proposed investigation of MPH treatment will not only further determine whether a potential pharmacological treatment restores cortical synapse dynamics in addition to fine motor function, but also will provide greater insight into the contribution of catecholaminergic neurotransmission to the neuropathology underlying fine motor dysfunction following developmental Mn exposure.